Abstract

IL-1R–associated kinase (IRAK)-M regulates lung immunity during asthmatic airway inflammation. However, the regulatory effect of IRAK-M differs when airway inflammation persists. A positive association between IRAK-M polymorphisms with childhood asthma has been reported. In this study, we investigated the role of IRAK-M in the susceptibility to adult-onset asthma and in chronic airway inflammation using an animal model. Through genetic analysis of IRAK-M polymorphisms in a cohort of adult-onset asthma patients of Chinese Han ethnicity, we identified two IRAK-M single nucleotide polymorphisms, rs1624395 and rs1370128, genetically associated with adult-onset asthma. Functionally, the top-associated rs1624395, with an enhanced affinity to the transcription factor c-Jun, was associated with a higher expression of IRAK-M mRNA in blood monocytes. In contrast to the protective effect of IRAK-M in acute asthmatic inflammation, we found a provoking impact of IRAK-M on chronic asthmatic inflammation. Following chronic OVA stimulation, IRAK-M knockout (KO) mice presented with significantly less inflammatory cells, a lower Th2 cytokine level, a higher IFN-γ concentration, and increased percentage of Th1 cells in the lung tissue than wild type mice. Moreover, lung dendritic cells (DC) from OVA-treated IRAK-M KO mice expressed a higher percentage of costimulatory molecules PD-L1 and PD-L2. Mechanistically, in vitro TLR ligation led to a greater IFN-γ production by IRAK-M KO DCs than wild type DCs. These findings demonstrated a distinctive role of IRAK-M in maintaining chronic Th2 airway inflammation via inhibiting the DC-mediated Th1 activation and indicated a complex role for IRAK-M in the initiation and progression of experimental allergic asthma.

Footnotes

This work was supported by grants from National Natural Sciences Foundation of China (81170040, 81470229, and 30470767, all to J.G.) and National Institutes of Health Grant K08HL135443 (to Y.B.). The sponsor had no role in study design, data collection and interpretation, and manuscript draft.